title: Glutamine therapy improves outcome of in vitro and in vivo experimental colitis models.
abstract: BACKGROUND
  Pharmacologic doses of glutamine (GLN) can improve clinical outcome following acute illness and injury. Recent studies indicate enhanced heat shock protein (HSP) expression is a key mechanism underlying GLN's protection. However, such a link has not yet been tested in chronic inflammatory states, such as experimental inflammatory bowel disease (IBD).
  
  
  METHODS
  Experimental colitis was induced in Sprague-Dawley rats via oral 5% dextran sulfate sodium (DSS) for 7 days. GLN (0.75 g/kg/d) or sham was administered to rats by oral gavage during 7-day DSS treatment. In vitro inflammatory injury was studied using YAMC colonic epithelial cells treated with varying concentrations of GLN and cytokines (tumor necrosis factor-α/interferon-γ).
  
  
  RESULTS
  Pharmacologic dose, bolus GLN attenuated DSS-induced colitis in vivo with decreased area under curve for bleeding (8.06 ± 0.87 vs 10.38 ± 0.79, P < .05) and diarrhea (6.97 ± 0.46 vs 8.53 ± 0.39, P < .05). This was associated with enhanced HSP25 and HSP70 in colonic mucosa. In vitro, GLN enhanced cell survival and reduced proapoptotic caspase3 and poly(ADP-ribose) polymerase cleavage postcytokine injury. Cytokine-induced inducible nitric oxide synthase expression and nuclear translocation of nuclear factor-κB p65 subunit were markedly attenuated at GLN concentrations above 0.5 mmol/L. GLN increased cellular HSP25 and HSP70 in a dose-dependent manner.
  
  
  CONCLUSIONS
  These data demonstrate the therapeutic potential of GLN as a "pharmacologically acting nutrient" in the setting of experimental IBD. GLN sufficiency is crucial for the colonic epithelium to mount a cell-protective, antiapoptotic, and anti-inflammatory response against inflammatory injury. The enhanced HSP expression observed following GLN treatment may be responsible for this protective effect.
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA. Hongyu.Xue@ucdenver.edu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Xue
authors.forename: Alexandra J D
authors.initials: AJ
authors.lastname: Sufit
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wischmeyer
mesh_terms: D000818:Animals; D019540:Area Under Curve; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003092:Colitis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D003967:Diarrhea / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005973:Glutamine / Q000494:pharmacology / Q000627:therapeutic use*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006470:Hemorrhage / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D016328:NF-kappa B; D005973:Glutamine; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3